This proposal is the Phase II renewal of an STTR award to Kardia Therapeutics undertaken in collaboration with Baylor College of Medicine (the home to Kardia's founding scientists). The project will accelerate the development and commercialization of human heart-derived cardiac progenitor cells (CPCs), to promote more effective regenerative growth in human heart disease. Ultimately, the goal is to improve patient morbidity and mortality in acute myocardial infarction and chronic heart failure. The Applicants'research is aimed at the further development of CPCs, which were found to exist in humans on the basis of key similarities to the mouse cardiac cells defined by stem cell antigen-1 (Sca-1). Phase I STTR support enabled the Applicants to begin translation of these findings to humans. The critical first step was successful preparation of the most auspicious subset-so-called "side population" cells-from human myocardium, resembling but distinct from the cells in bone marrow that account for most (if not all) long-term self-renewal and the fullest multi-lineage potential. The mission in Phase II is to obtain essential pre-clinical data-using the human CPCs for cardiac regeneration in immunodeficient or immunosuppressed recipient animals-to enhance the commercial potential of this strategy for heart repair. The Applicants'Specific Aims are to: 1. Assess the human CPCs'differentiation into cardiac muscle in culture, using treatments that trigger the cardiac phenotype in other precursor populations. 2. Assess the human CPC'differentiation into cardiac muscle in situ, following ischemia- reperfusion injury in immunodeficient mice. 3. Assess the human CPCs'differentiation into cardiac muscle in situ, following ischemia- reperfusion injury in immunosuppressed pigs. Thus, the critical objectives are to obtain vital proof that the human CPCs can be induced to create new cardiac myocytes, with specific emphasis on their fate when given as xenografted cells after experimental cardiac injury. Results of the proposed Phase II STTR studies will be pivotal to the commercial development of this potential therapy (autologous, at least initially), as well as pivotal to a successful FDA Biological IND filing.